VR1 is a receptor which exists in the primary afferent sensory nerve (mainly C fiber) and involved in the pain at various pathological condition. The said receptor is activated by capsaicin which is the main component of red pepper, and pain is induced thereby. It is known that not only the pain by capsaicin disappears in a VR1 deletion mouse but also hyperalgesia at the time of inflammation is attenuated [Nature, 405: 183-187 (2000)].
Capsaicin induces a pain by activating VR1 as described in the above, but it is known that it shows, on the contrary, an analgesic action by desensitizing an afferent nerve through the persistent activation and inhibition of the activation thereafter [Pharmacol. Rev., 51: 159-211 (1999); Drugs Aging, 18: 561-573 (2001)]. In fact, a capsaicin cream is used for the treatment of neuropathic pains such as postherpetic neuralgia and diabetic neuropathic pain and nociceptive pains such as rheumatic joint pain which is classified into inflammatory pains. On the other hand, it is known that not only the VR1 agonist but also the VR1 antagonist also shows analgesic action by inhibiting activation of the VR1 receptor. For example, it has been reported that a conventionally known VR1 antagonist, capsazepin, shows efficacy for neuropathic pain and inflammatory pain in animal models [J. Pharmacol Exp. Ther., 304: 56-62 (2003)].
As the diseases for which an agonist or antagonist for VR1 receptor could show efficacy, for example, neuropathic pains such as postherpetic neuralgia [Clin. Ter., 15: 510-526 (1993)], diabetic neuropathy [Arch. Intern. Med., 151: 2225-2229 (1991)] and the like, nociceptive pains such as joint pain [Clin. Ther., 13: 383-395 (1991)], postoperative pain [J. Pharmacol. Exp. Ther., 314: 410-421 (2005)], back pain [Pain, 106: 59-64 (2003)] and the like, headaches such as migraine [Cephalalgia, 20: 597-602 (2000)], cluster headache [Clin. J. Pain, 5: 49-53 (1989)] and the like, or cancer pain [J. Neurosci., 25: 3126-3131 (2005)] and fibromyalgia [Semin. Arthritis Rheum., 3: 41-47 (1994)] can be cited. Inhibitors for VR1 receptor activation are useful for the treatment of the diseases described above.
In addition, it is known that bladder function disorders are alleviated by injecting capsaicin or its analogous substance resiniferatoxin (RTX) into the bladder of a spinal cord injury patient and the like [J. Urol., 162: 3-11 (1999)]. This is considered to be based on desensitization of afferent nerve similar to the case of analgesic action. Accordingly, in addition to the bladder function disorders such as overactive bladder, urinary incontinence, neurogenic bladder, nocturia and the like, an inhibitor for VR1 receptor activation is also useful for a bladder dysfunction which accompanies prostate hypertrophy [Drugs Aging, 18: 561-573 (2001)]. In addition, a therapeutic effect for painful bladder syndrome [J. Urol., 176: 797-801 (2006)], interstitial cystitis [Can. J. Urol., 6: 737-744 (1999)] and chronic non-bacterial prostatitis [Eur. Urol., 48: 162-167 (2005)] by inhibiting activation of VR1 receptor has been suggested.
In recent years, studies have been making progress on the compounds having inhibitory action on VR1 activation. For example, it has been reported that the derivative represented by the following general formula, as a VR1 regulating agent, is useful for the treatment of pain and the like (Patent Reference 1).
(In the formula, Z represents C═O or N, V and U are independently a group selected from the class consisting of O, S, C═O, —CH2— and —NR2— [wherein R2 is H, C1-4 alkyl or the like], W is C or N, J is hydrogen or the like, L is —NH—C(O)—(CH2)q—, —C(O)—NH—(CH2)q— or the like [wherein q is 0 to 2], A ring is C3-7 cycloalkyl, phenyl or the like, R1 is independently C1-6 alkyl, C1-6 alkoxy, -halo, —CF3, —O—CF3, —NH2, —NH(C1-4 alkyl) or the like and n is 0 to 5, respectively. For details, see said official gazette.)
Also, it has been reported that the carboxamide derivative represented by the following general formula (III), as a VR1 regulating agent, is useful for the treatment of pain and the like (Patent Reference 2).
(In the formula, P is aryl, heteroaryl or the like, W, X and Y form a 5-membered nitrogen-containing hetero aromatic ring [wherein W, X and Y are selected from CR1a, NR1b, N, S and O], CR1a and NR1b are independently —H, alkyl or the like, R2 is independently —H, alkyl or the like, R3 is —H, halo, —NR4R5 or the like [R4 and R5 may be the same or different from each other and each represents —H or alkyl, or R4 and R5 may form a hetero ring together with the nitrogen atom to which they are bonded], r is 0, 1, 2 or 3, and s is 0, 1, 2, 3, 4, 5 or 6. For details, see said official gazette.)
Also, it has been reported that the derivative represented by the following general formula (IV), as a ligand for the VR1 receptor, is useful for the treatment of pain and the like (Patent References 3 and 4).
(In the formula, J is ═O or the like, X's are independently N or C, R1 is C2-6 alkyl, C1-6 alkyl which may be substituted, or the like, R2 is a saturated, partially saturated or unsaturated 9- or 10-membered bicyclic ring which contains 0, 1, 2 or 3 nitrogen atoms and 0, 1, 2 or 3 atoms selected from O and S [the total number of O and S atoms in the bicyclic ring does not exceed 2] and the bicyclic ring contains at least one N, O or S atom (the rest is omitted), and R3 is Re, C1-4 halo-alkyl, halo, (the middle is omitted), —NRaRa, —NRaC2-6alkylNRaRa or the like [Ra's are independently H or Rb, and Rb's are independently phenyl, benzyl or the like]. For details, see said official gazette.)
Though compounds having arylamide structure are disclosed in all of the Patent References 1 to 4 described in the above, there is no illustrative disclosure on a compound having a monoalkylamino group at the adjusting position of amido group on the aryl.
In addition, it has been reported that the quinoline derivative represented by the following general formula (V), as a regulatory agent of VR1 receptor, is useful for the treatment of pain and the like (Patent Reference 5).
(In the formula, R1 is hydrogen, hydroxy, halogen or the like, m is 0, 1 or 2, R2 is hydrogen or C1-8 alkanyl, L is a direct bond or the like, R3 is pyrrolyl, pyridyl, phenyl or the like, R4 is C1-12 alkanyl, —N(R5)(R6) [R5 is hydrogen or the like and R6 is C4-16 alkyl, alkanylcarbonyl, or C1-3 alkyl substituted with a group selected from the class consisting of pyrrolyl, pyridyl, furyl, thienyl and phenyl, or arylcarbonyl or the like] or the like, n is 1, 2 or 3 and Z is O or S, respectively. For details, see said official gazette.)
Also, a benzothiazole derivative characterized by its possession of VR1 receptor regulatory action and possession of hydroxymethyl group at the 2-position is disclosed in an international publication (Patent Reference 6) which was published after the application as the basis of the priority of the instant application.
In addition, a benzamide derivative characterized by its possession of VR1 receptor regulatory action and by substitution of a ring structure at the 4-position is disclosed in an international publication which was published by the applicant of the instant application, etc. (Patent Reference 7).
the nociceptin antagonist which comprises an amide derivative represented by the following general formula (VI) as the active ingredient has been reported (Patent Reference 8).
(In the formula, R1 and R2 may be the same or different from each other and each represents hydrogen atom, (lower alkyl group which may be substituted by hydroxyl group), amino group, lower alkylamino group or di(lower alkyl)amino group, R3 and R4 may be the same or different from each other and each represents hydrogen atom, halogen atom or lower alkyl group, ring A is aryl group or heterocyclic ring group, ring B is phenyl group or the like, E is single bond, —NR7— or the like [R7 is hydrogen atom or the like], ring G is aryl, heterocyclic ring group, cycloalkyl group or the like, R5 is halogen atom, hydroxyl group, di(lower alkyl)amino group or the like, t is 0 or an integer of from 1 to 5, m is 0 or an integer of from 1 to 8, and n is 0 or an integer of from 1 to 4. For details, see said official gazette.)
Though use of the nociceptin antagonist of said official gazette is for pain, there is no disclosure or suggestion therein on VR1 receptor. Though compounds having arylamide structure are disclosed in said official gazette, there is no illustrative disclosure on a compound having a monoalkylamino group at the adjusting position of amido group on the aryl.
In addition, 2-aminobenzamide derivatives having a bicyclic hetero ring on the nitrogen atom of amide group have been reported (Patent References 9 to 12). However, though angiogenesis inhibitory action and the like based on VEGF inhibition are disclosed in all of the references, there is no description on VR1 receptor and description on the application to pain. In addition, there is no disclosure in any of the official gazettes on a compound in which a monocyclic ring is directly bonded to the 2-position amino group without mediating an alkylene chain.
Patent Reference 1: International Publication No. 2004/108133
Patent Reference 2: International Publication No. 2004/072069
Patent Reference 3: International Publication No. 2005/072681
Patent Reference 4: US Patent Application Publication No. 2005/0165028
Patent Reference 5: International Publication No. 2004/069792
Patent Reference 6: International Publication No. 2006/038871
Patent Reference 7: International Publication No. 2004/110986
Patent Reference 8: Japanese Patent No. 3013989
Patent Reference 9: International Publication No. 2004/005279
Patent Reference 10: International Publication No. 2004/007457
Patent Reference 11: International Publication No. 2004/007458
Patent Reference 12: International Publication No. 2001/085671